The chemoprophylaxis of sexually transmitted diseases (STD) is an attractive concept. Intravaginally administered drugs might prevent infection at the portal of entry by inactivating the organism; blocking attachment of penetration; or interfering with specialized functions essential in disease pathogenesis. To facilitate development of prophylactic strategies for controlling STD we will pursue three specific aims: First, polysulfated carbohydrates and surface-active shown in Projects 1 and 2 to have minimal cell toxicity but potent in vitro activity against HSV and/or chlamydia will be studied to determine if they can protect guinea pigs against experimental genital infection. Intravaginal inoculation of guinea pigs with HSV or chlamydia results in infection remarkably similar to that observed in humans. These models have been useful in exploring microbial pathogenesis and should predict the efficacy of topical microbicides in women. Second, we will use HSV mutants engineered in Project 1 to explore aspects of the pathogenesis of genital herpes potentially important in the development of topical microbicides. Using mutants deficient in glycoprotein C (gC), a component of the viral envelope important for virion attachment, we will determine whether gC is important in the pathogenesis of genital infection. This information will establish whether gC is a potential target for microbicidal action. If intravaginal microbicide are to be effective in preventing genital herpes, they must block entry of virus into sensory neurons. Since nothing is currently known regarding how virus enters sensory nerves we will use gB and gD deficient mutants to examine whether HSV directly binds and penetrates sensory nerve endings or gains access via cell-to- cell spread from epithelial cells. Third, we will investigate the mechanism by which prophylactic treatment with a synthetic isomer of capsaicin, civamide, protects animals against genital herpes. Intravaginal capsaicin does not block viral replication nor directly inactivate HSV but appears to alter pathogenesis by interfering with specialized virus-neuron interactions. Even brief treatment with capsaicin results in a prolonged effect on the pathogenesis of genital herpes. Information gained from these experiments may allow development of new topically active neuropharmacological agents that will be effective in preventing genital HSV infection. Thus, the goals of our studies are to develop topical microbicides that warrant further evaluation in clinical trials and to examine aspects of the pathogenesis of genital herpes that might facilitate the rational development of intravaginal chemoprophylactic agents designed to prevent genital HSV infection.